Because of a possible causal relation between CMV infection and restenosis, as well as atherosclerosis, we explored the mechanisms of the interaction between CMV and SMCs. Animal species have evolved specialized inflammatory cells that generate reactive oxygen intermediates (ROIs) to defend against pathogen invasion. We hypothesized that SMCs can also activate an ROI program as an antiviral cellular defense mechanism. SMCs were infected with CMV and intracellular ROI levels were assayed by a dye that fluoresces upon oxidation. CMV infection markedly increased ROI levels, an effect mediated in part by NADH-oxidase (which is responsible for the neutrophile-mediated oxidative burst), the arachadonic acid cascade, and by xanthine oxidase. However, CMV has evolved counterstrategies to circumvent this SMC strategy to protect the organism from the lethal effects of the virus--thus, CMV actually depends on the SMC-induced ROIs for CMV gene expression, replication, and cytopathic effect. Finally, since antioxidants inhibit each of these processes, our results suggest new strategies for inhibiting CMV's potential contribution to atherosclerosis and restenosis.